G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4.
G protein-coupled receptor kinase 5 phosphorylation of hip regulates internalization of the chemokine receptor CXCR4.
复制标题
G蛋白偶联受体激酶5的HIP磷酸化调节趋化因子受体CXCR4的内在化。
DOI：
10.1021/bi2005202
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发表时间：
2011-08-16
期刊：
影响因子：
2.9
通讯作者：
Benovic, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Barker, Breann L.;Benovic, Jeffrey L.
G 蛋白偶联受体 (GPCR) 信号反应的幅度、持续时间和定位的调节是通过激活受体的脱敏、内化和下调来控制的。脱敏是通过 GPCR 激酶 (GRK) 对激活的受体进行磷酸化以及接头蛋白抑制蛋白的结合来启动的。除了磷酸化激活的 GPCR 之外，GRK 还可以磷酸化多种其他底物。新型 GRK 底物的体外筛选揭示了 Hsp70 相互作用蛋白 (Hip) 作为底物。 GRK5（而非 GRK2）在体外与 Hip 结合并以化学计量磷酸化。 GRK5 的主要结合域被定位到 Hip 上的残基 303-319，而磷酸化的主要位点被确定为 Ser-346。 GRK5 还与细胞中 Ser-346 上的 Hip 结合并磷酸化。虽然 Hip 之前被认为与趋化因子受体运输有关，但我们发现 Ser-346 的磷酸化对于激动剂诱导的趋化因子受体 CXCR4 的适当内化是必需的。总之，Hip 已被鉴定为体外和细胞内 GRK5 的新型底物，GRK5 对 Hip 的磷酸化在调节 CXCR4 内化中发挥作用。
Regulation of the magnitude, duration and localization of G protein-coupled receptor (GPCR) signaling responses is controlled by desensitization, internalization and down-regulation of the activated receptor. Desensitization is initiated by the phosphorylation of the activated receptor by GPCR kinases (GRKs) and the binding of the adaptor protein arrestin. In addition to phosphorylating activated GPCRs, GRKs have been shown to phosphorylate a variety of additional substrates. An in vitro screen for novel GRK substrates revealed Hsp70 interacting protein (Hip) as a substrate. GRK5, but not GRK2, bound to and stoichiometrically phosphorylated Hip in vitro. The primary binding domain of GRK5 was mapped to residues 303–319 on Hip, while the major site of phosphorylation was identified to be Ser-346. GRK5 also bound to and phosphorylated Hip on Ser-346 in cells. While Hip was previously implicated in chemokine receptor trafficking, we found that the phosphorylation of Ser-346 was required for proper agonist-induced internalization of the chemokine receptor CXCR4. Taken together, Hip has been identified as a novel substrate of GRK5 in vitro and in cells and phosphorylation of Hip by GRK5 plays a role in modulating CXCR4 internalization.
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